The CRISPR-Cas9 gene-edited therapy CTX001 has shown a consistent and sustained positive response in 10 patients treated for a pair of blood disorders—sickle-cell disease (SCD) and beta thalassemia—reported CRISPR Therapeutics and Vertex Pharmaceuticals the developers of the therapy. These are the first clinical studies of a CRISPR gene-editing candidate sponsored by U.S. companies.
According to data published last Saturday in the New England Journal of Medicine (NEJM) and presented Sunday at the annual American Society of Hematology (ASH) Meeting and Exposition, all seven patients with transfusion-dependent beta thalassemia (TDT)—including three who have either a severe or b0/b0 genotype—were transfusion independent at the last follow-up in the TDT trial, which is known as CLIMB-111 (NCT03655678).
In another trial assessing CTX001 in SCD, CLIMB-121 (NCT03745287), all three patients with SCD were free of vaso-occlusive crises (VOCs) from infusion with the therapy through last follow-up. These include Victoria Gray, an African-American SCD patient from Mississippi who has been followed for the past 18 months in a series of National Public Radio stories.
“We are pleased with the data presented at ASH, which demonstrate potential benefit and durability among a larger population of patients with transfusion-dependent beta thalassemia and sickle cell disease,” CRISPR Therapeutics CEO Samarth Kulkarni, PhD, said in a statement.
One analyst appears to share the enthusiasm of CRISPR Therapeutics (CRSP) and Vertex (VRTX) about CTX001. “Vertex looks like it has a potential blockbuster in due course and a potential ‘curative’ type gene-editing drug, which could be $1 [billion] type potential in the future,” Michael J. Yee, equity analyst with Jefferies, commented.
Yee also asserted that the updated data supported a long-term positive view on Vertex’s pipeline beyond cystic fibrosis, despite the company’s setback in October of halting development of Alpha-1 antitrypsin (AAT) deficiency candidate VX-814 after elevated liver enzymes were found in several patients, prompting a 20% drop in the company’s stock price: “We believe its overall approach of pursuing genetic and high unmet need areas is the right way to go.”
The positive data for CTX001 should lead investors to focus more attention on the program, Yee added.
“Science marches on”
Investors this morning rallied behind shares of CRISPR Therapeutics and other gene-editing therapy developers. As of 11:40 a.m., shares of CRISPR Therapeutics rose 10% to $162.61, while Intellia Therapeutics shares climbed 11% to $48.14; base editing drug developer Beam Therapeutics jumped 14% to $68.50; and Editas Medicine zoomed 19% to $40.89. Shares of Vertex, however, inched up 0.2% to $228.78.
“Science marches on. The ‘cure’ word being applied for the first time for these 2 common blood disorders for which there’s not even really a treatment,” tweeted Eric Topol, MD, director of the Scripps Research Translational Institute.
The new data comes more than a year after CRISPR Therapeutics and Vertex released preliminary, mostly positive safety and efficacy data from the first two patients enrolled in the two trials evaluating CTX001, an autologous ex vivo CRISPR-Cas9 gene-edited therapy designed as a one-time curative therapy for both TDT and SCD.
Through CTX001, a patient’s hematopoietic stem cells are edited to produce high levels of fetal hemoglobin (HbF) in red blood cells. This gene, active during gestation, is naturally shut down shortly after birth. CTX001 restores expression by interfering with an upstream regulatory pathway that typically keeps the HbF gene dormant. CRISPR Therapeutics and Vertex reason that the elevation of HbF by CTX001 has the potential to alleviate transfusion requirements for patients with TDT and reduce painful and debilitating sickle crises for patients with SCD.
TDT: Seven similar successes
The seven TDT patients whose data were reported at ASH had reached at least three months of follow-up after CTX001 dosing and therefore could be assessed for initial safety and efficacy, CRISPR Therapeutics and Vertex said. All seven showed a similar pattern of response, with rapid and sustained increases in total hemoglobin, fetal hemoglobin, and transfusion independence at last analysis.
All seven patients were transfusion independent with follow-up ranging from three to 18 months after CTX001 infusion, with normal to near normal total hemoglobin levels at last visit, including total hemoglobin ranging from 9.7 to 14.1 g/dL, and fetal hemoglobin ranging from 40.9 to 97.7%.
Bone marrow allelic editing data collected from four patients with six months of follow-up and from one patient with 12 months of follow-up after CTX001 infusion showed the treatment to have a durable effect, according to the companies.
The safety data from all seven patients were generally consistent with an autologous stem cell transplant and myeloablative conditioning. There were four serious adverse events (SAEs) considered related or possibly related to CTX001 reported in one patient: headache, hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome, and idiopathic pneumonia syndrome. All four SAEs occurred in the context of HLH and have resolved. Most of the non-serious adverse events were considered mild to moderate.
CLIMB-111 is an ongoing trial designed to assess the safety and efficacy of a single dose of CTX001 in patients ages 12 to 35 with TDT. The trial will enroll up to 45 patients and follow patients for approximately two years after infusion. To date, a total of 13 patients with TDT have been dosed with CTX001, including eight additional patients since the companies’ last update in June.
SCD: VOC-free three
The three SCD patients reported at ASH all reached at least three months of follow-up after CTX001 dosing and therefore could be assessed for initial safety and efficacy. All three patients showed a similar pattern of response, with rapid and sustained increases in total hemoglobin and fetal hemoglobin, as well as elimination of VOCs through last analysis.
All three patients remained VOC-free with follow-up ranging from three to 15 months after CTX001 infusion and had hemoglobin levels in the normal to near normal range at last visit, including total hemoglobin from 11.5 to 13.2 g/dL and fetal hemoglobin levels from 31.3 to 48.0%.
Bone marrow allelic editing data collected from one patient with six months of follow-up and from one patient with 12 months of follow-up after CTX001 infusion demonstrated a durable effect. The safety data were consistent with an autologous stem cell transplant and myeloablative conditioning. There were no SAEs considered related to CTX001, and the majority of non-serious adverse events were considered mild to moderate.
CLIMB-121 is an ongoing open-label trial designed to assess the safety and efficacy of a single dose of CTX001 in patients ages 12 to 35 with severe SCD. The trial will enroll up to 45 patients and follow patients for approximately two years after infusion. To date, a total of six SCD patients have been dosed with CTX001, including four additional patients since the June update.
Last Saturday, researchers from CRISPR Therapeutics, Vertex, and their clinical partners published the first peer-reviewed study on CTX001, “CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β Thalassemia,” in the New England Journal of Medicine. The study reported detailed data on the first patient with TDT enrolled in CLIMB-111 and the first patient with severe SCD enrolled in CLIMB-121, at 18 and 15 months of follow-up, respectively.
“Both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes,” the researchers reported. “After the administration of CTX001, both patients had early, substantial, and sustained increases in fetal hemoglobin levels with more than 99% pancellularity during a 12-month period.
“These findings, which indicate that CRISPR-Cas9–edited HSPCs underwent engraftment that was durably maintained, are consistent with an expected survival advantage of erythrocytes with a high level of fetal hemoglobin,” the study concluded.
Noting that elevated levels of fetal hemoglobin (HbF) are associated with improved morbidity and mortality in patients with TDT and SCD, the researchers manipulated hematopoietic stem cells to augment the production of HbF. The CTX001 treatment consisted of autologous CRISPR-Cas9–edited CD34+ hematopoietic stem and progenitor cells (HSPCs) that were genetically edited to reactivate the production of HbF.
Aiming to repeat the hereditary persistence of HbF, researchers used CRISPR-Cas9 gene-editing techniques in hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region of BCL11A to reduce BCL11A expression in erythroid-lineage cells, restore γ-globin synthesis, and reactivate production of fetal hemoglobin.
“These findings, which indicate that CRISPR-Cas9–edited HSPCs underwent engraftment that was durably maintained, are consistent with an expected survival advantage of erythrocytes with a high level of fetal hemoglobin,” the researchers concluded. “The clinical course of both patients supports our conclusion that CTX001 mimics the phenotype of hereditary persistence of fetal hemoglobin levels.”
“Beyond anyone’s wildest dreams”
Fyodor Urnov, PhD, director for technology and translation at the Innovative Genomics Institute at the University of California (UC), Berkeley, who was not connected with the study, offered high praise for the results on Twitter.
At 12 months, 80% of cells in the SCD patient and 64% in the TDT patient were marked in their marrow: “This is MAGNIFICENT!” tweeted Urnov, who is also a professor of genetics, genomics, and development at UC Berkeley. That and other data marked what he called a “huge win for the CMC [chemistry, manufacturing and control team and bodes VERY well for future of any ex vivo edited HSPC (hematopoietic stem/progenitor cell) approach.”
In a tweet thread Saturday, Urnov also enthused that HbF levels of 53% and 100% shown at 12 months in the SCD and TDT patients constituted “a success beyond anyone’s wildest dreams.”
“This creates further HUGE motivation to develop editing for sickle/thal to be scalable, more robust, and equitable. A comprehensive editing-based cure in the next decade is realistic and a key goal for a number of groups,” Urnov added—groups he said included IGI, Stanford Medicine, Editas, and Intellia.
The first SCD patient, 35-year-old Victoria Gray of Forest, MS, went home last year following her treatment with CTX001: “I feel hopeful for the future,” Gray said in October 2019 to NPR, which earlier chronicled Gray’s journey through CLIMB-121 after gaining exclusive access to the patient.
Said Kulkarni: “This is further validation of the potential of CTX001 to become a best-in-class therapy. We plan to continue the rapid advancement of our clinical trials to bring these much-needed therapies to patients.”
Vertex last year committed to developing treatments for TDT and SCD with CRISPR Therapeutics by agreeing to spend an additional up-to-$1.175 billion to expand the companies’ potentially $2.5 billion-plus collaboration launched in October 2015 to develop gene therapy-based treatments. The companies entered into an exclusive licensing agreement to discover and develop gene editing therapies for the treatment of DMD and DM1.
Since BCL11A is a repressor of γ-globin expression and HbF production in adult red blood cells, its down-regulation also holds promise as a therapeutic strategy for induction of HbF, according to a research group led by David A. Williams, MD, of Harvard Medical School and Boston Children’s Hospital.
Williams and colleagues on Saturday published “Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease,” a separate study in NEJM that validated BCL11A inhibition as an effective target for HbF induction, and offered preliminary evidence that gene knockdown based on a microRNA (shmiR) offered a favorable risk–benefit profile in sickle cell disease. Williams is the Leland Fikes professor of pediatrics at Harvard Medical School, chief of hematology/oncology at Boston Children’s Hospital, and senior vice president, CSO at Boston Children’s Hospital.
“A transformative treatment”
“Our vision with this approach is to use the patient’s own stem cells to provide a transformative treatment for these diseases, something almost unimaginable a few years ago. With these data in 10 patients, we can see the potential to fulfill this vision,” stated Haydar Frangoul, MD, medical director of pediatric hematology and oncology at Sarah Cannon Research Institute, within HCA Healthcare’s TriStar Centennial Medical Center. Frangoul was the lead author and a co-corresponding author for the NEJM study with Selim Corbacioglu, MD, associate professor, chair of the department of hematology, oncology, and stem cell transplantation, University Children’s Hospital Regensburg, Germany.
“With more data and longer duration of follow-up, we will hopefully confirm that we have a durable therapy that may transform the lives of many patients,” Frangoul added.
The U.S. Centers for Disease Control and Prevention (CDC) has estimated that SCD affects approximately 100,000 Americans. The CDC has no estimate for TDT but has noted that a subset of that disease, beta thalassemia, affects at least 1000 Americans, according to a patient website hosted by bluebird bio. SCD and TDT are types of hemoglobin disorders, a disease category to which more than 300,000 babies worldwide are born each year, according to the World Health Organization.
CTX001 has been granted Regenerative Medicine Advanced Therapy (RMAT), Fast Track, Orphan Drug, and Rare Pediatric Disease designations from the FDA for both TDT and SCD. CTX001 has also been granted Orphan Drug Designation from the European Commission for both TDT and SCD, as well as Priority Medicines (PRIME) designation from the European Medicines Agency (EMA) for SCD.
David Altshuler, MD, PhD, Vertex’s executive vice president, global research and CSO, told STAT: “When we looked at these data, and had the recent opportunity to get the latest update, there was a moment of silence.
“You realize that you are seeing for the first time the use of CRISPR in a human genetic disease actually playing out across a meaningful number of patients, and to envision not only what this means for these patients with sickle cell and beta thalassemia, but the potential of CRISPR for many more patients in the future.”